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The LRP Gene Encoding a Major Vault Protein Associated with Drug Resistance Maps Proximal to MRP on Chromosome 16: Evidence That Chromosome Breakage Plays a Key Role in MRP or LRP Gene Amplification¹

Department of Cytogenetics, City Of Hope National Medical Center, Duarte, California 91010 [M. L. S., J. P. H.], Cancer Research Laboratories, Queen's University, Kingston, Ontario K7L 3N6, Canada [S. P. C. C., R. G. D.]; Wyeth-Ayerst Research, Pearl River, New York 10965 [L. G.]; University Hospital Groningen, 9700 RB Groningen, the Netherlands [E. G. E. d. V.]; and Free University Hospital, 1081 HB Amsterdam, the Netherlands [H. J. B., G. L. S., R. J. S.]

A cDNA encoding the novel drug resistance gene, LRP (originally termed lung resistance-related protein), was isolated from HT1080/DR4, a 220-fold doxorubicin-resistant human fibrosarcoma cell line which displays a multidrug resistance phenotype and overexpresses the multidrug resistance protein (MRP) but does not overexpress P-glycoprotein encoded by the MDR1 gene. Using the full-length 2.8-kb cDNA probe, the gene for LRP was regionally localized to the 16p13.1-16p11.2 chromosomal segment in human metaphases. Dual color fluorescence in situ hybridization studies refined the localization of LRP to 16p11.2, a location approximately 27 cM proximal to MRP (16p13.1). Two color hybridization studies indicated that HT1080/DR4 fibrosarcoma cells contain amplification of both the MRP and LRP genes in a striking striped pattern in the homogeneously staining region, hsr(7)(p12p15). In contrast, only amplified MRP gene sequences were contained within the homogeneously staining region, hsr(18q). Amplification of LRP was not identified in any of seven other drug-resistant tumor cell lines characterized by 20–300-fold levels of doxorubicin resistance, including two cell lines known to overexpress LRP (SW1573/2R120 and GLC4/ADR). Amplified MRP gene sequences were identified in H69AR, GLC4/ADR, and HL-60/AR whereas only MDR1 gene amplification was observed in the S1B120 colon carcinoma cell line. These data indicate that although both the MRP and LRP genes map to the short arm of chromosome 16, they are rarely coamplified and are not normally located within the same amplicon. A key role for chromosome breakage in gene amplification is supported by the presence of non-random karyotypic anomalies near the MRP and LRP normal cellular loci.

¹ This work was supported in part by a grant from the Medical Research Council of Canada (S. P. C. C., R. G. D.). M. L. S. is a member of the City of Hope Cancer Research Center, which is supported by Public Health Service Grant CA-33572. S. P. C. C. is a Career Scientist of the Ontario Cancer Foundation and R. G. D. is the Stauffer Research Professor (Queen's University, Kingston, Ontario, Canada).

² To whom requests for reprints should be addressed, at City of Hope National Medical Center, Department of Cytogenetics, Northwest Building, Room 2255, 1500 East Duarte Road, Duarte, CA 91010-3000.

Received 6/29/95. Accepted 8/17/95.

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